Study to Investigate the Effect of BL-8040 (Motixafortide) on the QTc Interval in Healthy Subjects

Healthy Subjects Clinical Trial

Official title:

A Single-Dose, Randomized, Double-Blind, Placebo-Controlled, Positive-Controlled, Four-Way Crossover Study to Investigate the Effect of BL-8040 (Motixafortide) on the QTc Interval in Healthy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05293171
• Other study ID #: BL-8040.TQT.103
• Status: Completed
• Phase: Phase 1
• Start date: June 11, 2021
• Est. completion date: August 15, 2022

Study information

• Verified date: January 2023
• Source: BioLineRx, Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study will assess the corrected QT (QTc) effects (electrocardiogram [ECG]) of BL-8040 1.25 mg/kg (therapeutic dose) and 2 mg/kg (supratherapeutic dose) following a single subcutaneous (SC) injection relative to placebo in approximately 40 healthy subjects.

Description:

This is a randomized, double-blind (in respect to BL-8040 and BL-8040-matching placebo dosing), placebo- and positive-controlled, 4-period, 4-way crossover study in healthy subjects.

A continuous 12-lead cardiodynamic ECG recording will be collected for approximately 24 hours on Day -1 of Period 1 for use in the optimized individual corrected QTc (QTcI) baseline calculations.

On Day 1 of Period 1, subjects will be randomized to 1 of 12 treatment sequences. Each treatment sequence comprises 4 treatment periods.

On Day 1 of each period, subjects will receive single-dose SC injection of BL-8040 (therapeutic or supratherapeutic dose), single-dose SC injection of BL-8040-matching placebo, or a single oral dose of moxifloxacin. Cardiodynamic readings, plasma PK samples, and blood PD samples will be collected at different time points prior to dosing and up to 24 hours postdose in each period, as appropriate.

There will be a washout period of 5-7 days between dosing in each period.

All subjects who received at least one dose of any study drug (including subjects who terminate the study early) will return to the clinical research unit (CRU) 7 ± 2 days after the last dose for follow-up procedures, and to determine if any adverse event (AE) has occurred since the last study visit.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 38
• Est. completion date: August 15, 2022
• Est. primary completion date: June 1, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Healthy, adult, males and females between the ages of 18 and 55 years, inclusive, at Screening.

• Body weight between 50-109 kg (inclusive) and body mass index (BMI) within 18.0-29.99 kg/m2 (inclusive) at Screening.

• Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs or ECGs, as deemed by the PI or designee.

• Current non-smokers who have not used any nicotine-containing products (chewed or smoked) or replacement products including electronic cigarettes for at least 3 months prior to first dosing.

• Women must meet one of the following criteria: a) postmenopausal; b) surgically sterile; c) of childbearing potential and practicing contraception, as described below:

• Postmenopausal (postmenopausal women must have no menstrual bleeding for at least 1 year prior to first dosing and menopause is confirmed by FSH levels consistent with postmenopausal status), or

• Surgically sterile (e.g., hysterectomy, bilateral oophorectomy, hysteroscopic sterilization) for at least 6 months prior to first dosing, or

• Women of childbearing potential must be non-lactating and agree to either using a highly effective acceptable form of birth control (e.g., non-hormonal intrauterine device plus condom and spermicide).

• A non-vasectomized, male subject must agree to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days after the last dosing. (No restrictions are required for a vasectomized male provided his vasectomy has been performed 4 months or more prior to the first dosing. A male who has been vasectomized less than 4 months prior to study first dosing must follow the same restrictions as a non-vasectomized male.)

• If male, must agree not to donate sperm from the first dosing until 90 days after the last dosing.

• Understands the study procedures in the informed consent form (ICF), and is willing and able to comply with the protocol.

Exclusion Criteria:

• Past or present diseases, which, as judged by the PI or designee, may affect the outcome of this study or pose an additional risk to the subject by their participation in the study, including, but not limited to, significant medical abnormality including: psychiatric, neurologic, pulmonary, cardiac, gastrointestinal, genitourinary, renal, metabolic, endocrinologic, or autoimmune disorder.

• Is mentally or legally incapacitated or has significant emotional problems at the time of the Screening visit or expected during the conduct of the study.

• Positive result for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody at Screening.

• Family history of QTc prolongation or of unexplainable sudden death at <50 years of age.

• History or presence of any of the following:

• sick sinus syndrome, second or third degree atrioventricular block, myocardial infarction, pulmonary congestion, symptomatic or significant cardiac arrhythmia, prolonged QTcF interval, or conduction abnormalities;

• ischemic heart disease, symptomatic arrhythmias, or poorly controlled hypertension.

• Knowledge of any kind of cardiovascular disorder/condition known to increase the possibility of QT prolongation or history of additional risk factors for torsade de pointes (e.g., heart failure, clinically significant hypokalemia, family history of Long QT Syndrome or Brugada Syndrome) or cardiac conduction disorders.

• Any condition that may interfere with the absorption, metabolism, or elimination of the study drug.

• History of, or active, alcohol or illicit drug abuse as defined by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, manual, within 2 years prior to the first dosing. Alcohol abuse is defined as an average intake of two or more drinks (12 oz beer, 1.5 oz of hard liquor, or equivalent) per day.

• Laboratory safety test results that are outside of the normal reference ranges (unless clinically acceptable to the PI or designee) at Screening.

• Resting supine HR <50 bpm or >100 bpm at Screening or check-in (Day -2). Minor deviations will be acceptable if considered to be of no clinical significance by the PI or designee.

• Resting supine systolic blood pressure <90 mmHg or >140 mmHg; resting supine diastolic blood pressure <50 mmHg or >90 mmHg at Screening or check-in.

• Significant history or presence of ECG findings at Screening or check-in (Day -2), including:

• QTcF >450 msec

• QRS >110 msec, if >110 msec, result will be confirmed by a manual over read

• PR >200 msec

• Second or third-degree atrioventricular (AV) block.

• Significant history or presence of ECG findings as judged by the PI or designee at

Screening or check-in (Day -2), including:

• ECG abnormalities which interfere with accurate QT measurement

• T wave flattening or other abnormalities which in the opinion of the PI (or designee) may interfere with the analysis of QT intervals

• Any rhythm other than sinus rhythm, which is interpreted by the PI (or designee) to be clinically significant.

• Significant safety laboratory abnormalities that would place the subject at undue risk in the PI or designee's opinion, including but not limited to serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) >1.2 x upper limit of normal at Screening or check-in.

• Positive urine cotinine at Screening.

• Unable to refrain from or anticipates the use of:

• Any drug, including prescription and non-prescription medications, herbal remedies, or vitamin supplements beginning 14 days or 5 half-lives (whichever is longer) prior to the first dosing or likelihood that such treatment will be needed at any time during the study (unless approved in advance by the Sponsor). Medications listed in Section 11.4.2 will be allowed.

• Participation in another clinical study within 30 days prior to the first dosing. The 30-day window will be derived from the date of the last blood collection or dosing, whichever is later, in the previous study to Day 1 of Period 1 of the current study.

• Donation of blood or blood loss >500 mL within the 56 days prior to the first dosing.

• Plasma donation within 7 days prior to the first dosing.

• Any condition or situation that, in the opinion of the PI or designee, would prevent proper evaluation of the safety, PK, and/or PD of the study drug according to the study protocol (e.g., poorly compliant subject, poor venous access, allergies to medical plastics/latex/adhesive dressing/medical tape).

• History of hypersensitivity or allergy to moxifloxacin or any study medication.

• History of tendonitis or tendon rupture with moxifloxacin or any other quinolone type drug.

• History of unexplained loss of consciousness, unexplained syncope, near drowning with hospital admission.

• Use of any marijuana product within 6 months prior to the first dosing.

• Use of illicit drugs or tetrahydrocannabinol-containing medicines within 6 months prior to the first dosing.

• Female subjects with a positive pregnancy test at Screening or check-in or lactating.

• Positive urine drug or alcohol results at Screening or check-in.

• Has tattoo(s) or scarring at or near the site of injection or any other condition which may interfere with injection site examination, in the opinion of the PI or designee.

• Subjects intending to lose weight during the study.

Related Conditions & MeSH terms

• Healthy Subjects

Intervention

Drug:
• 1.25 mg/kg BL-8040 + BL-8040-matching placebo
Administered via subcutaneous (SC) injection
• 2 mg/kg BL-8040
Administered via subcutaneous (SC) injection
• BL-8040-matching placebo
Administered subcutaneous (SC) injection
• 400 mg Moxifloxacin (1x400 mg tablet)
Administered orally

Locations

Country	Name	City	State
United States	Celerion	Phoenix	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
BioLineRx, Ltd.	Celerion

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Evaluation of the PD effects (by assessing the peripheral blood CD34+ and peripheral blood receptor occupancy) of single therapeutic and supratherapeutic SC injections of BL-8040	Evaluations of CD34+ and receptor occupancy (RO) in the blood. CD34+ is provided as % or as absolute- Cells/uL. Receptor occupancy is provided as percentage.	Blood for PD (CD34+) is collected prior to study drug dosing and at 7 time points following each administration up to 24 hours . Blood for PD (RO) is collected prior to study drug dosing and at 5 time points following each administration up to 24 hours.
Primary	Assessment of the QTc effects of BL-8040 1.25 mg/kg and 2 mg/kg following a single SC injection relative to placebo in healthy subjects	Evaluation of the relationship between the plasma concentration of BL-8040 and ??QTcI (placebo adjustment for ?QTcI will be performed in the concentration-QTc model).	Continuous 24 hour cardiodynamic ECG recording on Day -1 (one day prior to dosing) of Period 1 (each period is 24 hours long)
Primary	Assessment of the QTc effects of BL-8040 1.25 mg/kg and 2 mg/kg following a single SC injection relative to placebo in healthy subjects	Evaluation of the relationship between the plasma concentration of BL-8040 and ??QTcI (placebo adjustment for ?QTcI will be performed in the concentration-QTc model).	Cardiodynamic ECG recordings on Day 1 (day of dosing) at different time points prior to dosing and up to 24 hours postdose in each period (each period is 24 hours long, a total of 4 periods)
Secondary	Evaluation of the safety (by assessing AEs, ECGs, vital signs, clinical lab tests, physical examination) and tolerability (by assessing AEs) of single therapeutic and supratherapeutic SC injections of BL-8040 in healthy subjects.	Evaluation of AEs, 12-lead safety ECGs, vital signs, clinical laboratory tests, and physical examinations.	Blood for BL-8040 PK is collected prior to dosing and at 13 different time points following dosing up to 24 hours
Secondary	Evaluation of PK of single therapeutic and supratherapeutic SC injections of BL-8040 in healthy subjects.	Evaluation of AUC0-t, AUC0-inf, AUC%extrap, Cmax, Tmax, for BL-8040, as appropriate.	Blood for BL-8040 PK is collected prior to dosing and at 13 different time points following dosing up to 24 hours
Secondary	Evaluation of assay sensitivity (i.e., to evaluate the effect of a positive control, a single oral 400 mg dose of moxifloxacin on the QTc interval in healthy subjects	Evaluation of the relationship between the plasma concentration of moxifloxacin and ?QTcI in order to demonstrate assay sensitivity	Blood for Moxifloxacin PK is collected prior to dosing and at 11 different time points following dosing up to 24 hours
Secondary	Assessment of the effects of single therapeutic and supratherapeutic SC injections of BL-8040 on non-QT interval ECG parameters	Time-point change from baseline, placebo-adjusted in ??QTcI. Time-point change from baseline, placebo-adjusted, for HR, RR, QTcF, PR, and QRS. Categorical outliers for HR, RR, PR,QRS, QTcI, and QTcF. Frequency of treatment-emergent changes in ECG morphology	Continuous 24 hour cardiodynamic ECG recording on Day -1 (one day prior to dosing) of Period 1 (each period is 24 hours long)
Secondary	Assessment of the effects of single therapeutic and supratherapeutic SC injections of BL-8040 on non-QT interval ECG parameters	Time-point change from baseline, placebo-adjusted in ??QTcI. Time-point change from baseline, placebo-adjusted, for HR, RR, QTcF, PR, and QRS. Categorical outliers for HR, RR, PR,QRS, QTcI, and QTcF. Frequency of treatment-emergent changes in ECG morphology	ardiodynamic ECG recordings on Day 1 (day of dosing) at different time points prior to dosing and up to 24 hours postdose in each period (each period is 24 hours long, a total of 4 periods)